The present invention relates to a novel prodrug of gemcitabine, which is capable of being given orally, traversing the intestinal tract substantially intact into the portal bloodstream with less gastrointestinal toxicity and better bioavailability than with the parent drug, and maintaining the efficacy of the parent drug at lower doses.
Gemcitabine hydrochloride (2′,2′-difluoro-2′-deoxycytidine hydrochloride) is an anti-tumor agent, with known antiviral action, that is currently produced and marketed as Gemzar®; a lyophilised, powder formulation for treatment of various cancers. Gemzar®, a process for making it and methods for using it are described in U.S. Pat. No. 5,464,826 and U.S. Pat. No. 4,808,614. Gemzar® is currently approved for the treatment of pancreatic cancer, breast cancer and non-small cell lung cancer (NSCLC) and is being evaluated for ovarian cancer. In addition Gemzar® may be used in the treatment of HCV as well as a modulator of immune function (see U.S. Pat. No. 6,555,518). Gemzar® is currently administered by intravenous infusion at a dose of approximately 1000 to 1250 mg/m2 over 30 minutes, once weekly for up to 7 weeks followed by a week of rest from treatment.
The use of gemcitabine orally may be limited by its poor oral bioavailability which is the result of first pass metabolism. Shipley L A. Et. al., “Metabolism and disposition of gemcitabine, and oncolytic deoxycytidine analog, in mice, rats, and dogs”. Drug Metabolism & Disposition. 20(6):849-55, 1992. In addition, when dosed orally, gemcitabine is implicated in causing adverse dose-limiting intestinal lesions characterized by moderate-to-marked loss of mucosal epithelium (atrophic enteropathy) throughout the entire length of the intestinal tract in mice given a single oral (gavage) gemcitabine dose of 167, 333, or 500 mg/kg. Horton N D et. al., “Toxicity of single-dose oral gemcitabine in mice”, American Association for Cancer Research, Poster Presentation, Orlando, Fla., Mar. 27-31, 2004. Comparable exposures via intravenous dosing in previous mouse studies did not result in death or gastrointestinal toxicity.
Methods for making prodrug and sustained released formulations of gemcitabine are well known in the art. Examples of such prodrugs and sustained released formulations can be found in WO 04/0412303 “Gemcitabine Prodrugs, Pharmaceutical Compositions and Uses Thereof”, Gallop et. al.; WO 98/32762 “Gemcitabine Derivatives,” Myhren, Finn, et al.; WO 02/09768 “Therapeutic polyesters and polyamides,” Uhrich, Kathryn E.; WO 02/76476 “Prodrugs of anticancer agents based on substituted aromatic acids,” Greenwald, Richard B., et al.; WO 02/65988, “Terminally-branched polymeric linkers and polymeric conjugates as prodrug,” Choe, Yun Hwang, et al.
Gemcitabine amide derivatives have been described in the art as useful intermediates in the synthesis of gemcitabine, see e.g. Britton, et al., U.S. Pat. No. 5,420,266 and Grindey, et al., U.S. Pat. No. 5,464,826. and also useful as prodrug moieties for the administration of gemcitabine, see e.g. Gallop, et al., WO 04/041203.
There continues to be a need for prodrugs of gemcitabine that will allow for oral delivery, will pass through the intestinal tract intact without substantial degradation and deliver gemcitabine to the afflicted area with acceptable safety and efficacy. Further, there continues to be a need for crystalline forms of such prodrugs suitable for pharmaceutical formulation and manufacture.
Surprisingly, we have discovered a novel crystalline form of an amide prodrug of gemcitabine which traverses the enterocyte substantially intact; is hydrolyzed to gemcitabine without significant accumulation of deoxydifluorouridine (dFdU) the predominant gemcitabine metabolite in the liver, has less toxicity than oral gemcitabine, and maintains appropriate efficacy and safety profiles when administered orally.